Project 3: The Evolving Role of Regional Lymph Nodes in Melanoma Progression

项目3摘要 癌症通常从其原发部位扩散，并在区域淋巴结(LN)上定居，代表着一种 是进步的标志，也是分期的关键参数。LN转移对预后的影响及临床应用 然而，微小转移性LN疾病患者的完整LN解剖因实体肿瘤类型而异 和患者子集。微小转移性淋巴结病切除不符合定义的临床观察 提高存活率突显了我们对区域淋巴结转移的理解上的差距，并引发了质疑 序贯转移的简单模型。鉴于淋巴结既是早期转移的部位，也是免疫学上的 对于器官，传播和免疫之间的相互作用可能是理解LNS如何影响的关键 结果。在这里，我们将研究肿瘤引流淋巴结的生物学，以询问区域引流淋巴结是否起到了 一个教育网站，最终改变了系统的大环境，有利于远处的肿瘤生长。 在这个提议中，我们检验了前哨LN经历一系列细胞和分子事件的假设 这使宿主能够接受肿瘤的进展。为了检验这一假设，我们将建立一个公正的、 区域排水LNS的时间和空间分辨率地图。这将使我们能够识别临床上相关的 通过整合对淋巴和LN的深入、机械性的理解来决定结果的机制 生物学以及高维成像和新的计算工具在老鼠和人类中的应用。要建造 在这张地图上，我们将利用新鲜冷冻的手术病例、存档的、FFPE匹配的原发和转移淋巴结 对，以及临床相关的小鼠模型，并确定支持肿瘤细胞种植的早期变化 黑色素瘤细胞首先到达LNS(目标1)。我们将进一步测试因果程序，包括类型 I干扰素信号，它可能在功能上启动这种肿瘤允许状态，并安装局部机制 适应性免疫抑制，限制全身免疫监视，从而限制远处转移(目标2)。 最后，我们将利用Core B的广泛资源和专业知识来研究免疫的效用 根据存档的前哨LN组织对患者风险进行分层的标记，从而预测II期和III期的复发 黑色素瘤患者(目标3)。我们在这里提出的工作有望极大地重新想象哨兵的角色 在系统性黑色素瘤进展中。这种观念的转变可能会为个性化的战略提供信息，以管理当地 疾病，从而调动抗肿瘤免疫和系统肿瘤控制跨实体肿瘤类型和 确定基于免疫的LN特征，以分层黑色素瘤复发的风险并指导临床护理。 通过这项提案产生的资源和知识将通过NYULH向公众开放 MetNet中心核心B和C，这将使这些观察扩展到其他实体肿瘤类型(例如， 乳腺癌)通过更广泛的转移研究网络，因此能够显著扩大 对LN转移和进展的认识。

PROJECT 3 SUMMARY Cancers commonly spread from their primary site and colonize regional lymph nodes (LNs), representing a hallmark of progression and a key parameter for staging. The prognostic impact of LN metastasis and utility of complete LN dissection in patients with micrometastatic LN disease, however, varies between solid tumor types and patient subsets. The clinical observation that removal of micrometastatic LN disease does not by definition improve survival has highlighted a gap in our understanding of regional LN metastasis and calls into question the simple model of sequential metastasis. Given that LNs are both an early site of metastasis and immunological organs, the interplay between dissemination and immunity may be critical to understanding how LNs impact outcome. Here we will investigate the biology of tumor-draining LNs to ask whether regional draining LNs act as an educational site that ultimately shifts the systemic macroenvironment to favor distant tumor outgrowth. In this proposal we test the hypothesis that sentinel LNs undergo a cascade of cellular and molecular events that prime the host to be receptive to tumor progression. To test this hypothesis, we will build an unbiased, temporally, and spatially resolved map of regional draining LNs. This will enable us to identify clinically relevant mechanisms that determine outcome by integrating a deep, mechanistic understanding of lymphatic and LN biology together with high-dimensional imaging and novel, computational tools in mice and humans. To build this map, we will leverage fresh frozen LNs from surgical cases, archived, FFPE matched primary and metastasis pairs, and a clinically relevant mouse model, and determine the early changes that support tumor cell seeding and the melanoma cell states that first arrive in LNs (Aim 1). We will further test causal programs, including type I interferon signaling, that may functionally initiate this tumor permissive state and install local mechanisms of adaptive immune suppression that limit systemic immune surveillance and thereby distant metastasis (Aim 2). Finally, we will leverage the extensive resource and expertise of Core B to investigate the utility of immune markers to stratify patient risk from archived sentinel LN tissue and thereby predict recurrence in Stage II and III melanoma patients (Aim 3). The work we propose here promises to significantly reimagine the role of the sentinel LN in systemic melanoma progression. This conceptual shift may inform personalized strategies to manage local disease and thereby mobilize anti-tumor immunity and systemic tumor control across solid tumor types and identify immune-based LN features to stratify risk for recurrence in melanoma and guide clinical care. The resources and knowledge generated through this proposal will be made publicly accessible through NYULH MetNet Center Cores B and C, which will enable extension of these observations to other solid tumor types (e.g. breast cancer) through the broader Metastasis Research Network and therefore enable a significantly expanded understanding of LN metastasis and progression.